The Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal dominant inheritance and a prevalence of approximately 1 per 5,000 population (Pyeritz, R. E. & McKusick, V. A. (1979) N Engl J Med. 300, 772-777). The syndrome shows no racial preference and both sexes are affected equally. It has been estimated that 25% of cases occur due to spontaneous mutations. While this condition shows high penetrance, marked interfamilial clinical variability is the rule (Pyeritz, R. E. et al. (1979) Birth Defects Orig Artic Ser. 15, 155-178). The lack of a specific biochemical or genetic marker of disease, coupled with the variability in clinical presentation, has frustrated diagnosis of equivocal cases and has likely contributed to a significant underestimation of the prevalence of disease.
The cardinal features of this disorder involve the ocular, skeletal, and cardiovascular systems. Cardiovascular pathology, including aortic root dilatation, dissection, and rupture, pulmonary artery dilatation, myxomatous valve changes with insufficiency of the mitral and aortic valves, and progressive myocardial dysfunction, is the leading cause of mortality in the MFS. The majority of fatal events associated with untreated MFS occur in early adult life. In a prospective study of 72 patients in 1972, the average age of death was 32 years (Murdoch, J. L. et al. (1972) N Engl J Med. 286, 804-808).
A recent reevaluation of life expectancy in the Marfan syndrome suggested that early diagnosis and refined medical and surgical management has greatly improved this situation (Silverman, D. I. et al. (1995) Am J Cardiol. 75, 157-160). Nevertheless, MFS continues to be associated with significant morbidity and selected subgroups are refractory to therapy and continue to show early mortality Morse, R. P. et al. (1990) Pediatrics. 86, 888-895; Sisk, H. E., et al. (1983) Am J Cardiol. 52, 353-358). In a review of 54 patients diagnosed during infancy, Morse et al. reported that 89% had serious cardiac pathology, and that cardiac disease was progressive despite standard care (22% died during childhood, 16% before age 1 year). In the more classic form of Marfan syndrome it is estimated that greater than 90% of individuals will have a cardiovascular ‘event’ during their lifetime, defined as the need for prophylactic surgical repair of the aortic root or death due to aortic dissection (Gillinov, A. M., et al. (1997) Ann Thorac Surg. 64, 1140-1144; discussion 1144-1145; Pyeritz, R. E. (1993) Semin Thorac Cardiovasc Surg. 5, 11-16; Silverman, D. I., et al. (1995) J Am Coll Cardiol. 26, 1062-1067; Gott, V. L., et al. (1999) N Engl J Med. 340, 1307-1313). Ocular and skeletal morbidity is less easily quantified (Maumenee, I. H. et al. (1981) Trans Am Opthalmol Soc. 79, 684-733; Magid, D., et al. (1990) AJR Am J Roentgenol. 155, 99-104; Sponseller, P. D., et al. (1995) J Bone Joint Surg Am. 77, 867-876). Approximately 60% of individuals with MFS have lens dislocation, often requiring surgical aphakia for optimal management. Retinal detachment and glaucoma can cause devastating visual impairment.
Skeletal involvement is evident in nearly all people with MFS. Progressive anterior chest deformity or scoliosis can cause cardiopulmonary dysfunction and commonly require surgical correction. Joint instability can cause physical disability and predispose to premature arthritis. Lung disease most commonly manifests with spontaneous pneumothorax and has been identified in 4-11% of MFS patients (Wood, J. R., et al. (1984) Thorax. 39, 780-784; Hall, J. R., et al. (1984) Ann Thorac Surg. 37, 500-504). Pathologic findings include upper lobe bullae with or without diffuse fixed obstructive airway disease that can be progressive and has traditionally been equated with destructive emphysema (Lipton, R. A., et al. (1971) Am Rev Respir Dis. 104, 924; Dominguez, R., et al. (1987) Pediatr Radiol. 17, 365-369) The majority of patients with MFS display a marked deficiency in skeletal muscle mass and fat stores despite adequate caloric intake and no evidence for malabsorption (Behan, W. M., et al. (2003) J Neurol Neurosurg Psychiatry. 74, 633-638; H. H., et al. (1973) Neurology. 23, 1257-1268; Gross, M. L., et al. (1980) J Neurol Sci. 46, 105-112; Joyce, D. A., et al. (1984) Aust N Z J Med. 14, 495-499). Evidence for skeletal muscle myopathy, including decreased strength and tone, has been observed in a subset of affected individuals and may contribute to decreased functional performance, respiratory insufficiency, ocular misalignment, and altered development of the skeleton including kyphosis and scoliosis.
An increasing challenge is to define the “new” natural history of MFS now that many individuals are surviving their predisposition for early aortic root dissection; already appreciated aging-associated phenotypes include a predisposition for dissection of the descending thoracic and abdominal aorta. Thus, despite advances in our ability to increase the length of life for many individuals with MFS, there is ample opportunity to improve the quality of life for the majority of affected individuals.
In 1991 a traditional positional-candidate analysis culminated with the demonstration of disease producing mutations in the FBN1 gene on chromosome 15q21.1 that encodes fibrillin-1 (Dietz, H. C., et al. (1991) Nature. 352, 337-339). Since that time, there has been generation and characterization of multiple mouse models of Marfan syndrome. This work has truly revolutionized the understanding of the pathogenesis of disease and has lead to exciting strategies for the treatment of the multi system pathogenesis of Marfan syndrome.
Many of the features of Marfan syndrome are common in the general population and represent a tremendous public health burden. These include aortic aneurysm (1-2% of the population at large), mitral valve prolapse (˜7%), emphysema (11%), scoliosis (0.5%), cataract (30%), arthritis (very common), and myopathy (many common genetic and acquired forms).
Accordingly, a need exists for methods and compositions for the treatment of Marfan syndrome and associated diseases, disorders and conditions, e.g., diseases, disorders and conditions associated with aberrant TGF-β expression.